Behavioral and neurochemical effects of alcohol on the developing brain 

PAUTASSI RM; CAMARINI R

Paris

Simposio; 2010 International Society for Biomedical Research on Alcoholism (ISBRA) World Congress; 2010

International Society for Biomedical Research on Alcoholism (ISBRA)

The general utility of animal models for tapping into the mechanisms underlying alcohol abuse and alcoholism has been long recognized. Among these models, the use of mice or rats selectively bred for expressing differential sensitivity to alcohol is a valuable tool. The use of immature animals provides yet another animal model. For instance, adolescent rats exhibit some of the traits observed in alcohol-preferring rat lines. Alcohol intake is much higher in adolescent than in adult rats (Doremus et al., 2005); and the developing brain of mice and rats is sensitive to positive and negative reinforcement effects of alcohol (Pautassi et al., 2009; Doremus-Fitzwater et al., 2010). An important benefit of working with an immature rodent model is that it provides a tool to analyze the mechanisms underlying (a) alcohol’s detrimental effects upon neurodevelopment, and (b) the effects of an early onset of alcohol drinking on later alcohol affinity. Early exposure to alcohol, either during pregnancy, infancy or adolescence, is a risk factor for the development of alcohol use disorders (DeWitt, 2000). The present symposium focuses on several aspects of the alcohol and development interaction, as scrutinized by behavioral and neurochemical approaches applied in animal models. The symposium will feature an international representation of speakers, with a mix between senior and junior scientists from different countries, including Argentina Brazil, United States and Spain. Maternal alcohol consumption during pregnancy allows early developmental alcohol exposure leading to several neurodevelopmental deficits, such as fetal alcohol syndrome (FAS). The symposium will begin with a summary of neuronal plasticity impairments frequently seen in animal models of FAS. Dr. Medina’s talk (“Improvement of SRF function is astrocytes can restore neuronal plasticity in a model of Fetal Alcohol Spectrum Disorders”) will then feature recent findings suggesting that these impairments are due to fetal alcohol altering the physiology of astrocytes, particularly the secretion of molecules by the serum response transcription factor. Dr. Medina will show promising approaches to restore this function by using viral-mediated gene transfer and ex vivo gene delivery. Adolescents tend to drink significantly more alcohol than adults, under a variety of testing circumstances (Doremus et al., 2005). This propensity has been linked to adolescents exhibiting age-specific patterns of responding to several acute effects of alcohol (e.g., sedation, motor coordination, hypothermia, narcosis; Spear and Varlinskaya, 2005; White et al., 2002). Age-related differences in motivational sensitivity to ethanol are also apparent, with adolescents being less sensitive to the aversive effects of ethanol (Anderson et al., 2008; Varlinskaya and Spear, 2008), yet more sensitive than adults to the rewarding consequences of the drug (Pautassi et al., 2008). The literature on the acute and repeated locomotor-activating effects of ethanol in adolescent animals is scarce and controversial. Yet recent work from Camarini’s group (Faria et al., 2008) suggests that adolescent mice may be less sensitive than adult mice to these effects. In this 2010 ISBRA symposium, Dr. Camarini [“Differential behavioral response to ethanol in adolescent mice: implication  for the role of camp-responsive element binding factor (Creb)”] will concentrate on recent, unpublished studies that confirmed Faria’s et al. (2008) finding of adolescent mice exhibiting either behavioral tolerance or no sensitization after repeated ethanol injections. A novel result was that adolescent but not adult mice showed decreased CREB activity in the prefrontal cortex after repeated ethanol. Thus, age-related differences in CREB signaling after ethanol exposure could be yet another factor leading to adolescents drinking more alcohol than their more mature counterparts. The discussion on age-related differences in physiological and behavioral effects of alcohol will continue during Dr. Varlinskaya’s talk (“Endogenous opioid systems and the social consequences of ethanol in adolescence”). Dr. Varlinskaya has extensively studied the effects of alcohol on social behavior during adolescence (Varlinskaya and Spear, 2007; 2008). Adolescent rats are extremely sensitive to the facilitating effects of low doses of alcohol on social behavior, yet relatively insensitive to alcohol’s socially suppressing effects, usually associated with the administration of higher doses. As with other age-related differences, this idiosyncratic pattern of responsiveness to alcohol’s consequences may put adolescents at risk for initiating or escalating alcohol use. During the symposium, Dr. Varlinskaya will review recent findings regarding the involvement of the endogenous opioid system in the mediation of these effects of alcohol. More in detail, the evidence suggests that ethanol-induced social facilitation in adolescents is related to an ontogenetically enhanced responsiveness of the endogenous mu opioid system, whereas attenuated sensitivity of the kappa opioid system may underlie the relative insensitivity of adolescents to the adverse effects of ethanol on social behavior. In general terms, the earlier adolescents start to drink, the higher the likelihood of alcohol abuse and dependence. This so-called “early debut effect” (Pedersen and Skrondal, 1998) has been repeatedly and consistently found in epidemiological studies (e.g., Grant and Dawson, 1997; DeWitt, 2000). Yet the attempt to model this effect in animal studies has proven troublesome. For instance, Slawecki and Betancourt (2002) found that extensive ethanol initiation during adolescence did not affect ethanol affinity in adulthood. A 3 or 10 day exposure to oral ethanol also failed to affect later operant self-administration of ethanol (Tolliver and Samson, 1991). The lack of a reliable animal model has hindered the study of the neurobiological mechanisms underlying the effects of an early onset of alcohol drinking. Recently, Guerri’s group at Valencia (Spain) has had some success in finding greater ethanol consumption after adolescent but not adult, initiation to alcohol. Specifically, the researchers found that chronic and intermittent ethanol treatment (3 g/kg) during adolescence not only caused cognitive deficits (Pascual et al., 2007) but also enhanced ethanol intake when tested during adulthood (Pascual et al., 2009. The successful establishment of this preparation has allowed Guerri and coworkers to analyze changes in neurotransmitters systems associated with chronic and intermittent alcohol exposure. The study of the consequences of chronic and intermittent ethanol exposure is important, since this mode of alcohol administration resembles the “binge drinking pattern” usually displayed by human adolescents. In the proposed symposium Dr. Pascual will give an overview of these findings, alongside with recent data regarding the effects of intermittent alcohol exposure during adolescence in the mesolimbic dopaminergic system and chromatin-remodelling modifications associated with the susceptibility of the adolescents to exhibit heightened alcohol consumption (title of Pascual’s contribution: “Behavioral and neurochemical changes associated with alcohol exposure during adolescence”). In summary, the symposium will offer an overview of current research on alcohol effects during development, with a focus on early development (i.e., fetal or adolescent periods) and age-related predispositions that may put subjects at risk for the development of alcohol use disorders. The distinct, yet related, objectives displayed in each contribution reflect the need to better integrate the alcohol and development fields. The organization of the proposed symposium will be a small, yet significant, step towards achieving this aim.